Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report.

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diabetes mellitus 4 endocrinologydiseases
metformin 11 endocrinologydiseasesdrugs
pioglitazone 69 endocrinologydiseasesdrugs
polycystic ovary syndrome 1 endocrinologydiseases
testosterone 2 endocrinologydiseasesdrugs
type 1 diabetes mellitus 1 endocrinologydiseases
type 2 diabetes mellitus 2 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
metformin 1356 utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per cent patients in north and south, respectively.
metformin 3359 Diabetes/Endocrinology of EMA concluded that pioglitazone was useful in the treatment of T2DM as second-line drug when metformin was not effective or contraindicated and that its use should be restricted in duration (less than two
metformin 10386 but duration of pioglitazone use was not specified.Pioglitazone was used mostly in combination with metformin and sulphonylurea, and the prescribed dose was 15-30 mg. In one study, it was used in combination with
metformin 10499 sulphonylurea, and the prescribed dose was 15-30 mg. In one study, it was used in combination with metformin , sulphonylurea and dipeptidyl peptidase-IV inhibitor at 15 mg/day dose[11]. In five studies patients
metformin 11965 pioglitazone in T2DM patients. Eight were monotherapy[43][44][45][46][47][48][49][50], one add-on to metformin [51], four add-on to sulfonylurea[52][53][54][55], and eight were add-on to sulphonylurea and metformin
metformin 12068 metformin[51], four add-on to sulfonylurea[52][53][54][55], and eight were add-on to sulphonylurea and metformin combination[56][57][58][59][60][61][62][63]. Two studies evaluated add-on to metformin, sulphonylurea
metformin 12155 sulphonylurea and metformin combination[56][57][58][59][60][61][62][63]. Two studies evaluated add-on to metformin , sulphonylurea and insulin[64][65]; three evaluated and noted decrease in α-amylase, glucokinase and
metformin 12740 comparable to PROactive studies. In one study, 7.5 mg of pioglitazone given with insulin, sulphonylurea, metformin and α-glucosidase inhibitor was found to be effective in achieving good glycaemic control[59].Table
metformin 17830 differences in drug utilization. In the GPRD (UK) database, pioglitazone is used most commonly with metformin at 30 mg[4]. The defined daily dose of pioglitazone is 30 mg[77]. In India, it is mostly used in combination
metformin 17954 The defined daily dose of pioglitazone is 30 mg[77]. In India, it is mostly used in combination with metformin and sulphonylurea at a dose of 15-30 mg/day[26][28]. There is also regional variation in pioglitazone
metformin 23132 India, pioglitazone is used more often as triple drug combination instead of dual drug therapy with metformin and at lower doses compared to UK. Compared to KPNC or French studies which found significant association
pioglitazone 384 Reproductive Health (ICMR), Mumbai, IndiaPublication date (ppub): 11/2016AbstractBackground & objectives:With pioglitazone ban and subsequent revoking in India along with varying regulatory decisions in other countries, it
pioglitazone 951 (PRISMA) guidelines, searching Medline/PubMed, Google Scholar and Science Direct databases using ‘ pioglitazone AND India AND human’ and ‘pioglitazone AND India AND human AND patient’ and compared with EMA-AR.
pioglitazone 994 Medline/PubMed, Google Scholar and Science Direct databases using ‘pioglitazone AND India AND human’ and ‘ pioglitazone AND India AND human AND patient’ and compared with EMA-AR. Spontaneous reports in World Health Organization
pioglitazone 1306 six publications, 26 (efficacy), 32 (drug utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per
pioglitazone 1571 The efficacy in clinical trials (CTs) was similar to those in EMA-AR. Incidence of bladder cancer in pioglitazone exposed and non-exposed patients was not significantly different in an Indian retrospective cohort study.
pioglitazone 1996 bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry
pioglitazone 2577 diabetes mellitus (T2DM). Reports about an increased risk of bladder cancer in patients exposed to pioglitazone led to its withdrawal from the French market[1]. The United States Food and Drug Administration (FDA)
pioglitazone 2835 but added a black box warning for bladder cancer risk[2]. Indian drug regulatory authorities withdrew pioglitazone in June 2013 but then revoked the ban due to lack of sufficient evidence and recommendation by the Drug
pioglitazone 3104 Medicines Agency (EMA) put forth an assessment report on safety, efficacy and risk management plan for pioglitazone in December 2011[4].The EMA assessed the association of pioglitazone with bladder cancer. The Scientific
pioglitazone 3173 efficacy and risk management plan for pioglitazone in December 2011[4].The EMA assessed the association of pioglitazone with bladder cancer. The Scientific Advisory Group in Diabetes/Endocrinology of EMA concluded that pioglitazone
pioglitazone 3285 with bladder cancer. The Scientific Advisory Group in Diabetes/Endocrinology of EMA concluded that pioglitazone was useful in the treatment of T2DM as second-line drug when metformin was not effective or contraindicated
pioglitazone 3813 the published literature from India to determine the efficacy, safety and drug utilization pattern of pioglitazone in patients with T2DM and compared it with the data from EMA-AR. The data from VigiBase, maintained
pioglitazone 3998 data from VigiBase, maintained by the World Health Organization Uppsala Monitoring Centre (WHO-UMC) on pioglitazone were also analysed.Material & MethodsThe systematic review was carried out according to the Preferred
pioglitazone 4302 databases, namely, Medline/PubMed, Google Scholar and Science Direct were searched and all studies on pioglitazone carried out in India published in English language between 1999 and 2014 were included.Study characteristics:
pioglitazone 4455 English language between 1999 and 2014 were included.Study characteristics: The search terms used were ‘ pioglitazone AND India AND human’ and ‘pioglitazone AND India AND human AND patient’ (Figure). The search was
pioglitazone 4498 included.Study characteristics: The search terms used were ‘pioglitazone AND India AND human’ and ‘ pioglitazone AND India AND human AND patient’ (Figure). The search was further expanded using other search terms
pioglitazone 5526 (i) that were carried out in Indian T2DM patients (and carried out in India) (population); (ii) with pioglitazone either alone or in combination with other antidiabetic drugs (intervention); (iii) comparing it with
pioglitazone 5928 such as cases of bladder cancer and utilization pattern such as prescribed dose and combination of pioglitazone (outcomes).Studies were excluded if related to pioglitazone use in other conditions such as (i) polycystic
pioglitazone 5988 such as prescribed dose and combination of pioglitazone (outcomes).Studies were excluded if related to pioglitazone use in other conditions such as (i) polycystic ovary syndrome; (ii) psoriasis; (iii) type 1 diabetes
pioglitazone 6624 (v) patient's age, body mass index, gender, duration of diabetes, co-morbidities; and (vi) the use of pioglitazone (dose, whether as monotherapy or in combination with other drugs). The overall use of pioglitazone (percentage)
pioglitazone 6723 pioglitazone (dose, whether as monotherapy or in combination with other drugs). The overall use of pioglitazone (percentage) in each region was calculated from the data provided in individual studies (usage and number
pioglitazone 7220 lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). The dose and duration of pioglitazone and also its effects on requirement of other antidiabetic drugs such as insulin and sulphonylureas,
pioglitazone 7500 following details about patients (case history): (i) age; (ii) gender; (iii) duration of T2DM; (iv) dose of pioglitazone ; (v) duration of pioglitazone use; (vi) investigations; and (vii) outcomes. Data from India were compared
pioglitazone 7530 history): (i) age; (ii) gender; (iii) duration of T2DM; (iv) dose of pioglitazone; (v) duration of pioglitazone use; (vi) investigations; and (vii) outcomes. Data from India were compared with the data and publications
pioglitazone 7886 freely available in the public domain and gives comprehensive information on benefit-risk evaluation of pioglitazone [4]. The drug utilization data from India were compared with that of the General Practice Research Database
pioglitazone 8217 PROactive study carried out in Europe[6][7]. Epidemiological studies on bladder cancer associated with pioglitazone from India were compared with Kaiser Permanente Northern California (KPNC) (USA)[8], French cohort study[9]
pioglitazone 8506 not have information on data from VigiBase. However, to get an estimate of spontaneous reports for pioglitazone , a summary of adverse drug reactions (ADRs) associated with pioglitazone was obtained from the WHO-UMC
pioglitazone 8579 of spontaneous reports for pioglitazone, a summary of adverse drug reactions (ADRs) associated with pioglitazone was obtained from the WHO-UMC VigiBase, global individual case safety report (ICSR) database through
pioglitazone 10302 to 1185, and duration of T2DM was from 0 to 1 year (newly diagnosed) to about 10 yr, but duration of pioglitazone use was not specified.Pioglitazone was used mostly in combination with metformin and sulphonylurea,
pioglitazone 11060 6.5-11 per cent of T2DM patients in inpatient departments[12][13][14][15][16]. The extent of the use of pioglitazone in outpatient departments (26 studies) was described as percentage of T2DM patients in 16 studies (Table
pioglitazone 11292 percentage of antidiabetic drug prescriptions in 10 studies (Table II). There was regional variation in pioglitazone use across India, being more in the north compared to the south (Table II).Table IPioglitazone utilization
pioglitazone 11864 and 13 non-randomized, controlled, comparative CTs) with primary objective to determine efficacy of pioglitazone in T2DM patients. Eight were monotherapy[43][44][45][46][47][48][49][50], one add-on to metformin[51],
pioglitazone 12563 done in younger patients, with shorter duration of T2DM, shorter trial duration, and lower dose of pioglitazone ; however, the decrease in HbA1c (efficacy) was found to be comparable to PROactive studies. In one study,
pioglitazone 12692 decrease in HbA1c (efficacy) was found to be comparable to PROactive studies. In one study, 7.5 mg of pioglitazone given with insulin, sulphonylurea, metformin and α-glucosidase inhibitor was found to be effective
pioglitazone 12880 was found to be effective in achieving good glycaemic control[59].Table IIIComparison of efficacy of pioglitazone in studies from India with PROactive studiesOther effects: Pioglitazone did not have any detrimental
pioglitazone 14497 patient died of metastasis to lung and liver, another had recurrence of haematuria on rechallenge with pioglitazone while one was in remission for 11 months after receiving six cycles of mitomycin chemotherapy. The outcome
pioglitazone 14797 carried out in India on 1077 diabetics with cancer, 20 were bladder cancer cases, of whom one was in the pioglitazone exposed group which consisted of 31 patients with exposure for more than two years and dose 7.5-15 mg/day.
pioglitazone 14962 exposure for more than two years and dose 7.5-15 mg/day. No significant association was found between pioglitazone use and bladder cancer[72]. In comparison, KPNC study (USA) which included 193,099 diabetic patients
pioglitazone 15120 KPNC study (USA) which included 193,099 diabetic patients found significant risk of bladder cancer in pioglitazone exposed patients with cumulative dose more than 28,000 mg and cumulative duration more than two years[8].
pioglitazone 15518 diabetics found no significant association[10] (Table IV).Table IVComparison of bladder cancer cases in pioglitazone -exposed and non-exposed patients in studies from India, United States of America, France and United
pioglitazone 15702 of America, France and United KingdomIn the WHO-UMC, VigiBase, there were 101 spontaneous reports on pioglitazone from India, most common ones being hypoglycaemia (19.8%) and oedema (19.8%) but none on bladder abnormalities
pioglitazone 15908 bladder abnormalities while globally there were 1862 reported cases of bladder carcinoma associated with pioglitazone .Other safety issues: In CTs, compared to baseline, significant increase in body weight (1.6±1.3 kg),
pioglitazone 16517 myocardial infarction, renal stone and fracture were reported in CTs[44][48]. Incidence of fracture in pioglitazone group (1.9%) was not significantly different compared to placebo group (1.9%) during a three-year study[48].
pioglitazone 16754 report a patient with Grave's disease and T2DM developed chemosis, proptosis and lid retraction while on pioglitazone with reversal on its discontinuation and treatment with steroids and surgical decompression[74]. Increased
pioglitazone 16958 decompression[74]. Increased micronuclei formation[75] and reversible atrial and mitral valve regurgitation with pioglitazone use[76] have also been reported.DiscussionWith pioglitazone being initially banned by the Indian drug
pioglitazone 17018 atrial and mitral valve regurgitation with pioglitazone use[76] have also been reported.DiscussionWith pioglitazone being initially banned by the Indian drug regulatory authority and later the ban being revoked, along
pioglitazone 17790 studies from India has brought out important differences in drug utilization. In the GPRD (UK) database, pioglitazone is used most commonly with metformin at 30 mg[4]. The defined daily dose of pioglitazone is 30 mg[77].
pioglitazone 17879 database, pioglitazone is used most commonly with metformin at 30 mg[4]. The defined daily dose of pioglitazone is 30 mg[77]. In India, it is mostly used in combination with metformin and sulphonylurea at a dose
pioglitazone 18053 metformin and sulphonylurea at a dose of 15-30 mg/day[26][28]. There is also regional variation in pioglitazone prescription with greater use in northern and western India compared to central and southern India with
pioglitazone 18395 exposure as in European population with higher dose and body weight has not been studied.Efficacy of pioglitazone has been studied in randomized and non-randomized comparative studies in India. The observed effects
pioglitazone 18851 epidemiological studies. In the French cohort study with large sample size, significant association between pioglitazone use and bladder cancer was noted even with more than one year of use[9]. In the KPNC study with smaller
pioglitazone 19221 28,000 mg, while in GPRD study, which was a propensity score matched study, no association between pioglitazone and bladder cancer was noted[8][10].Pioglitazone is metabolized mainly by CYP2C8[79], and any variation
pioglitazone 19995 it is 29.7 and 14.01-20.01, respectively[81]. Whether and how this background rate will affect the pioglitazone potential for carcenogenicity needs to be studied.Subsequent to the EMA assessment in 2011, 10 yr follow
pioglitazone 20247 KPNC cohort study final analysis with 10 yr follow up did not find significant association between pioglitazone and bladder cancer[82][83]. Though details are not yet published, there may be variables such as discontinuation
pioglitazone 20376 cancer[82][83]. Though details are not yet published, there may be variables such as discontinuation of pioglitazone to be considered.In CTs, case reports and spontaneous reports in the Pharmacovigilance Programme of
pioglitazone 20665 hypoglycaemia[48][73], all of which are listed in summary of product characteristics (SmPC) and EMA-AR for pioglitazone . Average weight gain in Indian trials (1.68 kg) had been lesser than in PROactive study (3.8 kg) which
pioglitazone 20830 been lesser than in PROactive study (3.8 kg) which may be because in Indian CTs[63][64][73] dose of pioglitazone was 7.5-30 mg/day while in PROactive it was 45 mg/day and duration of treatment was also longer[84].
pioglitazone 21533 significance has also not been established[49]. A case report of worsening of thyroid ophthalmopathy with pioglitazone use has been reported from India and this warrants caution in using pioglitazone in patients with thyroid
pioglitazone 21614 ophthalmopathy with pioglitazone use has been reported from India and this warrants caution in using pioglitazone in patients with thyroid abnormalities[74]. There are no published case reports and ICSRs in VigiBase
pioglitazone 21765 abnormalities[74]. There are no published case reports and ICSRs in VigiBase of macular oedema, a listed ADR for pioglitazone from India.As per the recommendation by DTAB in July-August 2013, Indian package inserts of pioglitazone
pioglitazone 21870 pioglitazone from India.As per the recommendation by DTAB in July-August 2013, Indian package inserts of pioglitazone containing products carry boxed warning contraindicating its use as a first-line therapy in diabetes
pioglitazone 22916 evidence for the various outcomes could not be sufficiently estimated.In conclusion, regional variation in pioglitazone use was observed in India, with higher use in north and west compared to south and central regions.
pioglitazone 23039 observed in India, with higher use in north and west compared to south and central regions. In India, pioglitazone is used more often as triple drug combination instead of dual drug therapy with metformin and at lower
pioglitazone 23288 KPNC or French studies which found significant association between incidence of bladder cancer and pioglitazone cumulative dose >28,000 mg and duration of use more than one year, in retrospective cohort study from
pioglitazone 23423 >28,000 mg and duration of use more than one year, in retrospective cohort study from India with 15-30 mg pioglitazone taken for more than two years, association between incidence of bladder cancer and pioglitazone use
pioglitazone 23519 mg pioglitazone taken for more than two years, association between incidence of bladder cancer and pioglitazone use was not seen. Smaller sample size, lower dose of pioglitazone and lower background incidence of
pioglitazone 23585 between incidence of bladder cancer and pioglitazone use was not seen. Smaller sample size, lower dose of pioglitazone and lower background incidence of bladder cancer might be some of the possible reasons for not finding
pioglitazone 23828 controlled CTs, though on fewer patients, at shorter duration of treatment and with lower dose, efficacy of pioglitazone on HbA1c and lipids was similar to that in PROactive studies. ADRs have not been reported to PvPI and
pioglitazone 24071 spontaneous reporting must be encouraged. Studies on compliance to warnings given in the package insert for pioglitazone and epidemiological studies with larger sample size and regional representation are needed
testosterone 16160 kg/m2), reduction in haemoglobin and compared to placebo reduction in total, free and bioavailable testosterone with increase in androstenedione were observed[44][49][55][65][73]. No significant change in liver function
testosterone 21328 women was noted, with 896 cases of fracture being reported in 22 randomised CTs[85]. Decrease in serum testosterone observed in one study from India was not reported in SmPC or EMA-AR, and its clinical significance has
Select Disease Character Offset Disease Term Instance
diabetes mellitus 611 carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR).Methods:Systematic
diabetes mellitus 2478 receptor gamma, acts as an insulin sensitizer, thereby improving glycaemic control in patients with type 2 diabetes mellitus (T2DM). Reports about an increased risk of bladder cancer in patients exposed to pioglitazone led to
diabetes mellitus 6093 pioglitazone use in other conditions such as (i) polycystic ovary syndrome; (ii) psoriasis; (iii) type 1 diabetes mellitus ; (iv) in vitro studies; and (v) reviews, commentaries and editorials.Drug utilization studies: The data
diabetes mellitus 21975 pioglitazone containing products carry boxed warning contraindicating its use as a first-line therapy in diabetes mellitus , use in patients with active bladder cancer and uninvestigated haematuria as well as discontinuation
polycystic ovary syndrome 6037 pioglitazone (outcomes).Studies were excluded if related to pioglitazone use in other conditions such as (i) polycystic ovary syndrome ; (ii) psoriasis; (iii) type 1 diabetes mellitus; (iv) in vitro studies; and (v) reviews, commentaries
type 1 diabetes mellitus 6086 to pioglitazone use in other conditions such as (i) polycystic ovary syndrome; (ii) psoriasis; (iii) type 1 diabetes mellitus ; (iv) in vitro studies; and (v) reviews, commentaries and editorials.Drug utilization studies: The data
type 2 diabetes mellitus 604 decided to carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR).Methods:Systematic
type 2 diabetes mellitus 2471 receptor gamma, acts as an insulin sensitizer, thereby improving glycaemic control in patients with type 2 diabetes mellitus (T2DM). Reports about an increased risk of bladder cancer in patients exposed to pioglitazone led to

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